Abstract
NGLY1 deficiency is an ultra-rare autosomal recessive disorder caused by loss of function variants in the NGLY1 gene, representing the first known congenital disorder of deglycosylation. The disorder is characterized by a range of core features, including global developmental delay and/or intellectual disability, hyperkinetic movement disorder, transient elevation of liver transaminases, hypo- or alacrima, and peripheral neuropathy. Additional symptoms such as microcephaly, hypotonia, EEG abnormalities, brain imaging abnormalities, GI disturbances, and a history of intrauterine growth restriction have been reported in some cases. NGLY1 gene mutations lead to reduced or absent N-glycanase 1 activity, resulting in the accumulation of abnormal glycoproteins within the endoplasmic reticulum and impairing protein quality control mechanisms. Diagnosis is primarily achieved through genetic testing, while the identification of the biomarker GlcNAc-Asn may facilitate diagnosis rates. Treatment options are currently limited to supportive care, although gene therapy is being developed. To advance understanding and intervention in NGLY1 deficiency, participation in patient registries, natural history studies, and interventional research is crucial. Genetic counseling is strongly recommended for carriers and individuals at risk, with consideration given to DNA preservation for future evaluations and targeted treatments.
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N-glycanase 1 (NGLY1) deficiency is an ultra-rare, autosomal recessive disorder caused by loss of function variants in NGLY1 [1]. It is categorized as the first known congenital disorder of deglycosylation [2]. The disorder is characterized by five core features: (1) global developmental delay and/or intellectual disability, (2) a primarily hyperkinetic movement disorder (3) transient elevation of liver transaminases (4) hypo- or alacrima, and (5) peripheral neuropathy [1, 3, 4].
Additionally, acquired microcephaly, hypotonia, EEG abnormalities with or without overt seizures, brain imaging abnormalities, GI disturbances, and a history of intrauterine growth restriction (IUGR) were also reported in some cases. Some patients were noted to have dysmorphic features, but overall these were not considered to be particularly prominent [1]. The differential diagnosis of inherited conditions featuring alacrima and neurological dysfunction is limited, and we did not identify any other disorder associated with both alacrima and choreoathetosis [1].
In NGLY1 deficiency, the mutations in the NGLY1 gene result in reduced or absent N-glycanase 1 activity. This leads to the accumulation of abnormal glycoproteins within the ER, disrupting the normal protein quality control mechanisms. As a result, the misfolded proteins cannot be properly degraded and cleared from the cells.
At present, the condition is diagnosed via genetic testing. However, screening for the recently described NGLY1 Deficiency biomarker, GlcNAc-Asn, may help identify patients and increase the rate of diagnosis [5]. To determine the severity of the illness and the requirements of a person with NGLY1 deficiency the evaluations necessary for initial diagnosis include radiological and orthopedic assessment including DXA scan, neurologic and neurodevelopmental evaluation of cognitive abilities, ophthalmologic evaluations for hypolacrima and lacrimal disease, GI evaluations of transaminase levels, and constipation.
Treatment options are presently limited to supportive care. However, a gene therapy is currently under development. Thus, it is increasingly important to identify affected families to participate in patient registries, natural history studies, and interventional studies [6].
We strongly believe that genetic counseling should be offered to young adults who are carriers or at risk of being carriers. It is crucial to determine genetic risk, confirm carrier status, and explore prenatal or preimplantation genetic testing options before planning for pregnancy. Preservation of DNA should be considered which allows for re-evaluation and the possibility of identifying genetic causes that were previously unknown, thereby offering renewed hope for accurate diagnoses and targeted treatments.
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Zainab Hasan conceived the manuscript. Both authors were major contributors in writing the manuscript. Both authors read and approved the final manuscript.
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Hasan, Z., Warsi, S.M.F.A. Shedding light on NGLY1 deficiency: a call for awareness and support. J Rare Dis 2, 20 (2023). https://doi.org/10.1007/s44162-023-00024-9
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DOI: https://doi.org/10.1007/s44162-023-00024-9